Virtual combinatorial library design

Liu, D., Jiang, H., Chen, K. and Ji, R. A New Approach to Design Virtual Combinatorial Library with Genetic Algorithm Based on 3D Grid Property. J. Chem. Inf. Comput. Sci., 1998, 38, 233-242. 

HTS data as well as virtual screening can guide and direct the design of combinatorial libraries. A genetic algorithm (GA) can be applied to the generation of combinatorial libraries [18. The number of compounds accessible by combinatorial synthesis often exceeds the number of compounds which can be syiithcsii ed... 

In general, the described techniques provide an effective, flexible, and relatively fast solution for library design based on analysis of bioscreening data. The quantitative relationships, based on the assessment of contribution values of various molecular descriptors, not only permit the estimation of potential biological activity of candidate compounds before synthesis but also provide information concerning the modification of the structural features necessary for this activity. Usually these techniques are applied in the form of computational filters for constraining the size of virtual combinatorial libraries and... 

Closely related to the use of PSA in virtual screening is its application in the design of combinatorial libraries with optimal properties. These applications are reviewed further in Refs. [46, 47], for example. 

The next vague of tools will be around computational or in silico ADME approaches. These will allow to include ADME into the design of combinatorial libraries, the evaluation of virtual libraries, as well as in selecting the most promising compounds to go through a battery of in vitro screens, possibly even replacing some of these experimental screens. Several of these computational tools are currently under development as will be discussed in this volume. 

The concepts of molecular similarity (1-3) and molecular diversity (4,5) play important roles in modern approaches to computer-aided molecular design. Molecular similarity provides the simplest, and most widely used, method for virtual screening and underlies the use of clustering methods on chemical databases. Molecular diversity analysis provides a range of tools for exploring the extent to which a set of molecules spans structural space, and underlies many approaches to compound selection and to the design of combinatorial libraries. Many different similarity and diversity methods have been described in the literature, and new methods continue to appear. This raises the question of how one can compare different methods, so as to identify the most appropriate method(s) for some particular application this chapter provides an overview of the ways in which this can be carried out, illustrating such comparisons by,... 

Bradley and coworkers used the 3D pharmacophore ensemble model to filter a virtual combinatorial library of 3924 N-substituted glycine peptoids (30) containing three known a, actives down to a set of 639 products. Using a cut-down technique, a 160 compound combinatorial library was designed in which the number of compounds that passed the ensemble model filter was maximized. This library contained two of the three known actives present in the original 3924 compound virtual library. This represents a substantial enrichment [(2 actives/160 products) X 100 = 1.25% vs (3 actives/3924 products) x 100 = 0.076%]. 

Fig. 2.3. Virtual combinatorial library is the start point for any combinatorial library design. It consists of libraries from individual reactions. Compounds from a given reaction share a unique product core.

Schneider, G. (2002) Trends in virtual combinatorial library design. Curr Med Chem 9, 2095-2101. 

Varnek, A., Fourches, D., Solov ev, V.P. et al. 2004. In Silico design of new uranyl extractants based on phosphoryl-containing podands QSPR studies, generation and screening of virtual combinatorial library and experimental tests. J. Chem. Inf. Comput. Sci. 44 (4) 1365-1382. 

G. Wolber, T. Langer. Comb Gen a novel software package for the rapid generation of virtual combinatorial libraries. In Rational Approaches to Drug Design, H.-D. Holtje and W. Sippl (eds), Prous Science, Barcelona, Spain, 2000, pp. 390-399. 

In collaboration with University of Trieste, we have developed rational approaches for the design and synthesis of peptidomimetic and non-peptidic inhibitors of HIV PR, utilizing structure-based [12-15], as well as combinatorial, library design methods [16, 17]. In this paper, we survey computer-assisted studies on the design, focusing and in silico screening of virtual combinatorial libraries of peptidomimetics and cyclic ureas, as potential anti-HIV agents, that were carried out in our laboratory. 

When the three-dimensional structure of the target receptor is known, receptor-based techniques can be applied to combinatorial library design. We adapted the combiBUILD program from the original BUILDER program to generate and evaluate these virtual combinatorial libraries. It was developed for the case where the orientation of the scaffold in the active site is known, and therefore focuses on examining the conformations of the... 

The so-called sparse libraries are now the norm, designed by creating larger virtual combinatorial libraries and then removing the unattractive or undesirable... 

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